7-hydroxy coumarin derivative



July 5, 1966 H. RITTER ETAL 7-HYDROXY COUMARIN DERIVATIVE Original Filed July 26, 1962 b5 7o min 75 FIG.|

In ming-Fes 066.153,26 vgjwmvgm Doof C.. mcCf INVENTORS HEINRICH RITTER Rum BEYERLE BY ROLF -EBERHARD NW1 FRANCE M. CRAWFORD United States Patent Office Patented July 5, 1966 9 Claims. (cl. 26o-343.2)

This application is a division of parent application Serial No. 212,657, tiled July 26, 1962.

The administration of coronary vasodilators is to bring about an enhanced blood ow in the coronary vessels. The conventional coronary vasodilators, however, involve the disadvantage of exercising merely a non-specific vasodilator action on the coronary vessels because they simultaneously cause a dilatation of other large blood vessel areas, which is symptomatic of a considerable decrease in blood pressure. This hypotension does not allow the use of the known coronary vasodilators in hypotonic patients and in those having an acute myocardial infarction. In such cases the known agents may even evoke a paradoxical effect on the coronary vessels, namely a coronary blood flow decreasing effect (see Scheler and Bretschneider, Verhandlungen der deutschen Gesellschaft fr Kreislautforschung, vol. 26, page 254 (1960)). Moreover, the known coronary vasodilators have only a relatively short-term action.

Consequently, the objective of our interest has been directed to the development of such coronary vasodilators as specifically dilate the coronary vessels only and, thus, do not exhibit a hypotensive action and which especially possess a long-term activity.

Now, we have found that the desired properties inhere in the derivatives of the 7-hydroxy-coumarins of the general formula wherein R1 is a substituent of the group consisting of a hydrogen atom, an alkyl, alkenyl, aryl, aralkyl, heteroalkyl, aminoalkyland a carbalkoxyalkyl radical, R2 is a substituent of the group consisting of an alkyland aryl residue, R3 is a substituent of the group consisting of an alkenyl, carbalkoxyalkyl, carboxyalkyl, carbamidoalkyl radical and, if R1 is an aminoalkyl radical, furthermore an alkyl radical and R4 is a substituent of the group consisting of a hydrogen atom and the residue -OR3.

The new 7-hydroxy-coumarin derivatives are obtained in the known methods by allowing 7-hydroXy-coumarins of the general formula wherein R4 is a hydrogen atom or a hydroxyl group, to react with halogen compounds of the formula RSHal, in the presence of an acid-binding agent, or by condensing with cyclization substituted hydroxy-cinnamic acids of the general formula R30 OH or their functional derivatives or by condensing oxybenzenes of the general formula R30 -OH with -keto-acid esters of the general formula :Elli Rr-(I-CH-oooalkyl or, if R3 has the meaning of a carbamido-alkyl radical, by aminating 7-hydroXy-coumarin derivatives of the general formula alkyl-COO-alkylene-O O with ammonia or primary or secondary amines.

The 7-hydroxy-coumarins being required, interalia, as starting products may be obtained according to known methods, by condensing in the presence of an acid condensation agent -keto-acid esters of the general formula being correspondingly substituted with hydroxybenzenes of the general formula and the blood pressure was measured in the femoral artery by means of an Anderson-Glass-Capsule Manometer. During the test period the animals were given articial respiration. On these test conditions the dilatation of the Vcoronary artery being caused by the test substance, gives rise to a more .rapid bubble flow, whereas a constriction of the coronary vessels becomes evident from a retardation of the bubble ow, which is recorded by a kyrnograph. In all these tests there was used papaverine as a comparative standard substance.

FIGURES l and 2 illustrate graphically the results obtained when using different amounts of papaverine in Curve I represents the action of 0.4 mg./kg. papaverine,

Curve II represents the action of 0.8 mg./kg. papaverine,

Curve III represents the action of 0.8 mg./kg. 3-,8-

diethylamino-ethyl-4-methy1-coumarin-7-ethyl oxyacetate chlorhydrate,

Curve IV represents the action of 1.265 mg./ kg. 3-,8-

diethylarnino-ethyl-4-rnethy1-coumarin-7-ethyl oxyacetate chlorhydrate,

Curve V represents the action of 2 mg./ kg. 3-[3- diethylamino-ethyl-4-methyl-coumarin7-ethyl oxyacetate chlorhydrate,

FIGURE 1 indicates the inuence of the substance upon the coronary flow and FIGURE 2 the influence upon the blood pressure. The data forming basis of the diagram represent the mean value of the results of measurement ascertained in tests on 8 animals each. The administration of doses higher than 0.8 mg./kg. papaverine is impossible because otherwise a too sharp decrease in `blood pressure occurs. The figures show the clear superiority of the hydroxy-conmarin derivative under our invention over the standard substance papaverine which, on the one hand lies in the degree of the influence upon the coronary flow and on the other hand, in the duration of this influence (see FIGURE l) and, furthermore, they show the difference in the change of blood pressure (see FIGURE 2).

On the same test conditions some further substances of our invention had pharmacologically been tested and the mean values of the test results obtained are indicated in the following table.

4 +=having the same action as papaverine and ++=having an action intenser and longer than papaverine For clinical investigation there has been used especially the 3--diethylaminoethyl-4-methylcoumarin-7-ethyl oxyacetate chlorhydrate. In various clinics the preparation was administered both in the form of drages and in the form of solutions for intravenous and intramuscular injection in the case of most diversified clinical appearances. The drages were administered in a dosage of 15-50 milligrams three times daily and the intravenous solution was given in a dosage of 10-20 milligrams once daily. In none of the cases, side-elects of the substance had been observed. The following diagnoses had been made in the patients singled out for these tests: hypercholesterinemia, coronary sclerosis, myocardial infarction, stenocardia, cardiosclerosis, coronary insufliciency and angina pectoris gravis. In practically all of the cases under examination a signicant improvement in the Maximum LD50, Dosage, increase Duration Change Substance g./kg. mg./kg. in the of action 1n blood mouse i.v. coronary in minutes pressure,

110W, percent percent Papaverine i.v. 0.033- 0. 8 24 8 -20 3diethylaminoethyl-4methy1coumarin i.v. 0.034 0. 8 22 60 +2 7ethyl oxyacetate chlorhydrate. (2;65 S-B-pyrrolidinoethyl-4-methylcou1narin-7- i.v. 0.04-- 1. 0 53 26 :1:0

ethyl oxyacetatc chlorhydrate. 3--piperidinoethy14-methylcoumarin7 1.v. 0.016. 0. 2 26 19 +2. 2 ethyl oxyacetate chlorhydrate. 0. 4 37 28 -0. 5

1. 0 74 50 i0 3--morpholinoethyl-4-methylcoumarin-7- i.v. 0.11. 1. 0 21 16 i0 ethyl oxyacctute chlorhydrate. 3-piperidinoethylA-methyH-allyloxycou- Lv. 0.048- 1. 0 94 3D +11. 3

marin chlorhydrate. B--diethylaminoethyl-4-phenylcournarn-7 1.y. 0.02. 1. 0 88 40 1 -15 ethyl oxyacetate chlorhydrate. 3-[1.3bis-(diethylamino)-isopropyl]-4 l.v. 0.058. 0. S 43 65 methy1coumarin7-ethyl-oxyacetate chlorhydrate. 3-diethylaminoethyl4-methylcoumarm-7 2. 0 130 40 oxyacetic acid an1i.noethylamide.

l Until 10 minutes after the injection, later 10%.

Furthermore, comparative tests had been made on the same conditions as described before, however, with intracoronary administration of the following substances and papaverine in equal dosages.

state of health of the patients was observed, which led to a complete redress of their pains and complaints.

In the preparation of drages and tablets containing as active ingredient the 7-hydroXy-coumarin derivatives of our invention, these substances may be admixed with solid tabletting adjuvants, such as starch, lactose, talc and the like. Any of the tabletting materials used in pharmaceutical practice may be employed. For the preparation of the injection solutions there are particularly suited the derivatives of the 7-hydroxy-coumarins being basically substituted since they are water-soluble in the form of their salts. Injection solutions of water-insoluble products may of course .be prepared in the conventional manner by concurrently using well-known suspending agents, emulsitiers and/ or solubilizers.

The following examples are given for the purpose of characterizing the substances of `the present invention. All temperatures given are in degrees centigrade.

Example 1 14.3 grams 4-phenyl-7-hydroxy-coumarin (prepared according to the method specied in Org. Synth. vol. 21, page 23 by condensation of benzoylacetic acid ethyl ester with resorcin in concentrated sulfuric acid) are dissolved in 150 ccm. methylethyl ketone and admixed With 10 grams anhydrous potassium carbonate. This mixture is stirred for one Ihour at 70 and then 13 grams bromoacetic acid ethyl ester and 0.5 grams potassium iodide are added. It is heated until boiling and stirred for 8 hours at the boil. The reaction mixture is iltered 01T with suction in the heat and the filtrate is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride, washed several times with diluted allowed to react with 18.5 grams bromoacetic acid ethyl ester according to Example 1. Thus, 4-methyl-coumarin- 7-ethyl-oxyacetate having a melting point of 98-100" are obtained,

Yield: 19 grams=72.5% of the theory.

Example 4 grams 3-phenyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of resorcin with a-phenyl-acetoacetic acid ethyl ester as indicated in J. Chem. Soc. 109, 110 and I. Chem. Soc. 127, 1983) yare suspended in 200 ccm. methylethyl ketone and admixed with 20 grams anhydrous potassiunm carbonate. The mixture is stirred for one hour at 70 and then 15 grams chloroacetic acid tert. butyl ester are allowed to drop in. Subsequently, it is heated until boiling and stirred for another 9 hours at the boil. New the reaction mixture is filtered oli with suction in the heat and the iiltrate is concentrated in the vacuum. The residue is dissolved in methylene chloride, the solution is Washed for several times with diluted sodium hydroxide solution and, subsequently, the methylene chloride solution is concentrated in the vacuum to dryness. The remaining raw Iproduct is recrystallized from benzine.

Yield: 20 grams 3-phenyl-4-methyl-coumarin-7-tert. butyl oxyacetate having a melting point of 113-115 (=69% of the theory).

In an analogous manner, there may be prepared the following 7-oxy-coumarin derivatives:

Starting materials Final product Melting Yield,

point percent 3-phenyl-4-methy1-7-hydroxy- Chloroaeetic acid-isopropyl ester.. 3-phenyl-4-methyl-coumarin-7- 13S-140 70 eoumarin. isopropyl oxyacetate. 3-ethyl-4-phenyl-7-hydroxy- Chloroacetic acid-tert. butyl ester S-ethyl-4-phenyl-coumarin-7-tert. 122-123 64 coumarin. i butyl oxyacetate.

Do Chloroacetic acid-isopropyl ester-- SethyM-phenyI-coumarin-7-iso- 124-125*1 77 l propyl oxyacetate. 3-benzyl-t-methyl--hydroxy- Bromoacetic acid-ethyl ester B-benzyl--methyl-eoumarin-L 117-120u 66 coumarin. ethyl oxyacetate.

sodium hydroxide solution and the solution of methylene chloride is evaporated to dryness. The raw products may be recrystallized from ethyl acetate for further purication. White needles having a melting point of 137-138" are obtained.

Yield: 14 grams 4-phenyl-coumarin-7-ethyl oxyacetate (=71.8% ofthe theory).

Example 2 18 grams 3-butyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of a-:butylacetic acid ethyl ester with resorcin according tothe method specied in Org. Synth. vol. 21, page 23) are suspended in 200 ccm. methylethyl ketone. 12 grams anhydrous potassium carbonate are added and the mixture is stirred for 1 hour at 70. Then 0.5 gram potassium iodide are introduced into the reaction mixture and 16 grams bromoacetic acid ethyl ester are allowed to drop in. The mixture is heated until -boiling and stirred for 8 hours at the boil. Then the reaction mixture is filtered off with suction in the heat and worked up as indicated in Example 1. The raw product may -be recrystallized from ethyl acetate for further purication. The 3-butyl-4-methyl-coumarin-7-ethyl oxyacetate thus obtained forms White needles having a melting point of 78.

Yield: 20 grams=83.5% ofthe theory.

dissolved in 180 ccm. methylethyl ketone and, Whilst adding 16 grams anhydrous potassium carbonate, they are Example 5 12 grams 3-allyl-4-methyl-7-hydroxy-coumarin are dissolved in ccm. methylethyl ketone and admixed with 12 grams anhydrous potassium carbonate. This mixture is stirred for 1 hour at 70 and then 11 grams bromoacetic acid ethyl ester are allowed to drop in. Then thev mixture is stirred under reflux for another 9 hours. According to the recipe indicated in Example 1, 3-allyl-4- methyl-coumarin-7-ethyl oxyacetate having -a melting point of 12-44" is obtained in a good yield.

Example 6 18.7 grams 3--diethylaminoethyl-4methyl7hydroxy coumarin chlorhydrate are dissolved in 200 ccm. methylethyl ketone and 18 grams anhydrous potassium carbonate are added. The mixture is stirred for 1 hour at 70 and then 12 grams fbromoacetic acid ethyl ester are allowed to drop in. The reaction mixture is stirred under redux for 9 hours and then it is filtered oit with suction lin the heat. The filtrate is concentrated in the vacuum to dryness and the resultant residue is dissolved in ether. The etheric solution is washed with diluted caustic soda solution for several times and, subsequently, dried with Glaubers salt. By introduction of hydrochloric acid gas into the etheric solution the reaction product is precipitated in the form of chlorhydrate.

Yield: 15 grams 3 13 diethylaminoethyl-4-methylcoumarin-7-ethyl oxyacetate chlorhydrate having a melting point of 154-156 (=63% of the theory).

According to the process described in this example there may be prepared in an analogous manner the following compounds of the general formula marin5.7di(ethyl oxyacetate) having a melting point of 11G-112 (=57.5% of the theory).

l Example 8 Ri l grams 3 diethylaminoethyl 4 methyl coumarin-7-ethyl oxyacetate chlorhydrate are stirred together RaO- /-O o with 75 grams ethylene diamine for about 1,5 hours at -25". The resultant colorless precipitate is ltered 01T Melting 10 with suction, washed with water and dried. Thus, 8 grams R, R, R3 point of 3--diethylaniinoethyl-4-methyl-coumarin-7-oxyacetic acid aminoethylamide are obtained which, after recrystallization from Water, are colorless crystals having a melting oint of 118119 -dictlr laminoeth vl Meth l Eth l 220-222 P 01V 113iI iss-201 15 When using concentrated ammonia instead of ethylene D0 do 28s-290 p pipedinthyl" do 22H22, diamine, there 1s obtained in an analogous manner the diethylammoefhyi Piieiiy1- 15s-160 3--diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid q pipednoethyl 20H09., arriide in the form of colorless crystals having a melting s-morpiliiiinoetilhyli poi-235 point of 186-187 -pyrroi irioc 1y 82-1 3 v dimethymmiuopmpy! ISOSZ, 20 When using in this example instead of ethylene diamine, 13a-bis(dietiiyiaiiiiiim-iso- 176 one of the following amines, the corresponding amides of pwpyl. the 3--diethylaminoetliyl-4-methyl-coumarin-7-oxyacetic acid are obtained:

Amine used Final product Melting point Asymmetric diethylethylene 3--diethylamino-ethyl-4-methyl-coumariri-7- 122-124 amine. oxyacetic acid diethylaminoetliylamide. Hexamethylene diamine 34E-diethylarninoethy14-rnethylcoumarin7- 194 oxyacetic acid @Caminohexylamde -y-Dimethyl-amino-propyl- :HS-diethylaminoethyl4-metliyl-coumarin7 120 amine. oxyzcetic acid-7'-dimethyl-aminopropyl- H111 C. Butylamine 3--diethylnrninoethylA-niethyl-coumarinJ- 129 oxyacetic acid butylamidc. a-Amiuo-pyridine 3-/3-diethylaminoethylA-niethyl-coumarin-7 1GO-161 oxyacetic acid o/-pyridylamidel The 3 diethylaminoethyl 4 methyl couniarin- 7ethyl oxyacetate chlorhydrate described in this example can be saponied to the free acid in a known method by dissolving 4 grams of the chlorhydrate in 40 ccm. water and heating this solution for 4 hours under reux. When subsequently concentrating the aqueous solution in the vacuum to dryness, a white crystalline residue is obtained which represents the 3--diethylaminoethyl-4-methy1-coumarin-7-oxyacetic acid chlorhydrate having a melting point of 70-75. The yield of the saponication is quantitative.

Example 7 14 grams 3carbethoxymethy1-4-methyl-5,7dihydroxy coumarin (prepared by condensation of phloroglucine with acetylsuccinic acid diethyl ester according to the method indicated in Chemical Abstracts Vol. 37, 14302 (1943)) are suspended in 200 ccm. methylethyl ketone and 20 grams anhydrous potassium carbonate are added. This mixture is stirred for 1 hour at 70 and then 20 grams bromoacetic acid ethyl ester are allowed to drop in.

Then the mixture is heated until boiling and stirred for 9 hours at the boil. The reaction mixture is ltered olf with suction in the heat and the ltrate is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride and washed for several times with diluted caustic soda lye. After drying, the methylene chloride layer is concentrated in the vacuum to dryness and the residual raw product is puried by recrystallization from a mixture of ethyl acetate/benzine (1:1).

Yield: 13 grams 3carbethoxymethyl-4-methyl-cou- Example 9 18.7 grams 3--dietliylaminoethyl-4-methy1-7-hydroxycoumarin-chlorhydrate are suspended in 280 com. methylethyl ketone and, after the addition of 20 grams anhydrous potassium carbonate, the mixture is stirred for 4 hours at 70. Subsesquently, a solution consisting of 9 grams, N,Ndimethylchloroacetamide in 25 ccm. methylethyl ketone is allowed to drop into the reaction mixture and is stirred for 8 hours at 70.

After cooling, the solution is filtered off with suction and the iiltrate is concentrated in the Vacuum to dryness; the residue is dissolved in ethyl acetate and washed for several times with diluted sodium hydroxide solution. The ethyl acetate layer is eliminated and dried. Hydrochloric acid gas is introduced into this solution for precipitating the chlorhydrate of the final product. Thus, 3--diethylaminoethyl-4-methyl-couinarin-7-oxyacetic acid dimethylamide chlorhydrate is obtained having a melting point of 203-206.

Yield: 14 grams=59% of the theory.

In an analogous manner, there is obtained the 3-di ethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid dibutylamide chlorhydrate having a mleting point of 129- 130 by allowing 3--diethylaminoethyl-4-methyl-7-hydroxy-coumarin-chlorhydrate to react with N,Ndibuty1 chloroacetamide.

It will be understood that this invention is susceptible to further modification and, accordingly, it is desired to comprehend such modifications within this invention as may fall within the scope of the appended claims.

9 We claim: 1. A compound of the formula C Ha wherein X is selected from the group consisting of amino, lower alkylarnino, lower dialkylamin-o, .amino lower alkylamino, and lower dialkylamino lower alkylarnino.

C Ha

3. 3 a diethyiaminoethy1-4-methyl-coumarin-7-oxyacetic acid amide having -the formula C Ha 4. 3 ,8 diethylaminoenhy1-4methyl-courmarinJ-oxyacetic acid I8'-diethylam'moethylamide having the formula 10 6. 3 diethylaminoethyhl-niethyl-coum'arin-7oXy acetic acid fydimethy1aminopropy1amide having the formula 9. 3 diet'hylamin0ethy1-4-methy1-coumarin-7-oXyacetic acid dibutylamidc having the lformula l C 2H5 No references cited.

WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

JAMES A. PATTEN, Assistant Examiner'. 

1. A COMPOUND OF THE FORMULA 